While idiopathic pulmonary fibrosis (PF) is a devastating lung disease, the management of PF including effective monitoring of disease progression remains a challenge. Our previous study demonstrated that recombinant mouse SCGB3A2 exhibits anti-fibrotic activity in bleomycin-induced pulmonary fibrosis model mouse. We applied this mouse model in conjunction with the use of SCGB3A2 to introduce and validate a novel, fast, and ultrasensitive metalloproteinase (MMP) activatable optical probe, named MMP-P12, to noninvasively monitor pulmonary fibrosis (PF) progression and response to PF treatment. The MMP-P12 probe is a substrate for MMPs and contains a fluorescent dye and a quencher dye, which fluoresces only when the quencher dye is cleaved by MMPs. The use of MMP-P12 in PF model is based on the fact that MMPs such as MMP2 are thought to be highly expressed in fibrotic tissues. A bleomycin (BLM)-induced mouse PF model was subjected noninvasively to optical imaging at various time points after BLM treatment. The mouse PF model developed fibrosis during 21 days of the experimental period, and the progression of PF was well correlated with the stepwise increase of MMP2 expression as examined by quantitative RT-PCR and Western blot analysis on 7-, 14-, and 21-day post-BLM administration. On these days, MMP-activated fluorescence images were acquired in vivo and ex vivo. Signal quantification showed time dependent lung-specific incremental increases in fluorescence signals. As a treatment for PF, SCGB3A2 was administered intravenously daily for five days starting on day seven of BLM administration, which resulted in reduced MMP2 activity and reduction of PF. Importantly, the fluorescence signal that reflected MMP activity also decreased in intensity. In conclusion, MMPs may play an important role in PF development and the MMP-P12 probe could be a promising tool for PF detection, even at an early stage of the disease as well as an indicator of therapy response. The MMP-P12 may provide a promising tool for detection and/or assessment of PF progression.